Bibliographic details of the publications alphabetically referred to in this specification are collected at the end of the description.
Currently, no single treatment method is completely effective against HIV infections. Combination therapies, using drugs that target a number of different aspects of HIV replication, have proven to be the most effective way of ameliorating AIDS symptoms and prolonging life expectancy (Barry et al, 1998; Deeks, 1998; Miles, 1997; Miles, 1998; Moyle et al, 1998; Rachlis and Zarowny, 1998; Vell et al, 1997; Volberding and Deeks, 1998; and Volberdin, 1998). For example, a measure of success has been achieved with drugs targeting the viral reverse transcriptase and protease enzymes (Miller and Sarver, 1997; Mitsuya, 1992; Moore, 1997; and Thomas and Brady, 1997).
The protein Vpu forms an ion channel encoded by HIV and has a number of known roles in the virus life cycle including down-regulation of cell surface expression of the CD4 virus receptor molecule, control of the exit of gp160 from the endoplasmic reticulum and its delivery to the cell surface and regulation of virion budding from the cell surface membrane. In the absence of Vpu, HIV replication has been shown to be severely retarded in monocytes and macrophages (Balliet et al, 1994; and Westervelt et al, 1992).
Nevertheless, Vpu has been labelled as an “accessory” protein of HIV because none of its known functions appear to be essential for virus replication in vitro.
To improve the prospect of treating and preventing HIV infection, there is an on-going need to identify molecules capable of inhibiting various aspects of the HIV life cycle. In work leading up to the present invention, the inventors have surprisingly determined that despite current dogma, viral replication (and in particular HIV replication) can be retarded by inhibiting or otherwise down-regulating Vpu ion channel functioning. Further, the inventors have also determined that although the drug amiloride has no effect on HIV replication, amiloride analogues, in which the H2N group located at the 5-position of the pyrazine has been substituted, inhibit Vpu function and thereby inhibit the continuation of the HIV life cycle.